Tumor calcification and sustained complete response after chemoembolization in hepatocellular carcinoma: Two case reports and review of literature

Abstract

BACKGROUND

Transarterial chemoembolization (TACE) is a widely accepted palliative therapy modality for unresectable hepatocellular carcinoma (HCC). Although it is rarely curative, complete radiological response can be achieved in selected patients, leading to prolonged survival. Post-treatment tumoral calcification is an uncommon imaging finding in HCC and is rarely reported after drug-eluting beads TACE (DEB-TACE).

CASE SUMMARY

Two patients with large, solitary HCCs (> 5 cm) were treated with DEB-TACE, and both achieved complete radiological response after two treatment sessions. Approximately 1 year after DEB-TACE, imaging demonstrated progressive peripheral tumoral calcification. Over 6 years of follow-up, both patients remained in remission with preserved liver function.

CONCLUSION

These two cases highlight the potential for complete remission and long-term survival in selected patients with large HCC following DEB-TACE. The appearance of peripheral calcification may represent a late imaging marker of effective tumor necrosis and durable treatment response although prospective studies are warranted to clarify its prognostic value.

Key Words: Hepatocellular carcinoma; Transarterial chemoembolization; Drug-eluting beads chemoembolization; Complete response; Remission; Tumoral calcification; Case report

Core Tip: Tumoral calcification following transarterial chemoembolization (TACE) for hepatocellular carcinoma is a rare imaging finding, and its clinical significance remains unclear. This case report describes 2 patients with large hepatocellular carcinoma who developed complete radiological response after drug-eluting beads TACE, followed by progressive peripheral calcification and sustained disease-free survival for 6 years. The notable association between post-TACE calcification and long-term remission raises the possibility that calcification may serve as a late imaging biomarker of effective tumor necrosis and durable treatment response.

INTRODUCTION

Hepatocellular carcinoma (HCC) is one of the most prevalent solid tumors and the fourth-leading cause of cancer-related mortality worldwide[1-4]. Surgical resection, liver transplantation, and image-guided ablation remain the only widely accepted potentially curative options[5-8]. However, the majority of patients present at advanced stages or with impaired hepatic reserve, making them ineligible for these treatments[9-11].

For such patients transarterial chemoembolization (TACE), transarterial radioembolization, and systemic therapies are recommended, providing palliative benefit and improved survival[12,13]. Among these TACE is the most frequently employed locoregional therapy for unresectable HCC[14,15]. Its safety and efficacy have been validated in multiple randomized controlled trials, and it is endorsed by major clinical guidelines as the standard first-line treatment for intermediate-stage disease[15-17]. In routine practice, however, TACE is applied across the entire disease spectrum, from very early to advanced stages[18-20]. Outcomes remain heterogeneous, largely influenced by tumor burden, liver function, and procedural technique with reported median survivals ranging from 13 to 43 months[20-22].

The Barcelona Clinic Liver Cancer (BCLC) staging system is the most widely adopted framework for guiding HCC management, integrating tumor burden, liver function, and performance status into evidence-based treatment recommendations and prognostic prediction[6]. Within this system TACE is designated as the standard first-line therapy for intermediate-stage disease, characterized by asymptomatic patients with large or multifocal tumors and preserved liver function without macrovascular invasion or extrahepatic spread[12]. The updated BCLC system also incorporates the concept of treatment stage migration, allowing TACE in selected early-stage patients unsuitable for resection or ablation as well as its use as a bridging or downstaging strategy to liver transplantation. Consequently, in real-world practice a considerable proportion of TACE procedures are performed beyond the intermediate stage, reflecting the adaptability of the BCLC framework to diverse clinical scenarios[12,23].

Post-treatment tumoral calcification is a rare phenomenon that has been reported following HCC locoregional therapies. It has been described after radioembolization and very rarely after TACE. In conventional TACE, however, the detection of calcification is often obscured by lipiodol deposition[24-27]. To my knowledge progressive calcification following drug-eluting beads TACE (DEB-TACE), particularly in association with durable remission, has not been previously reported. Herein, I report 2 patients with large solitary HCCs who underwent DEB-TACE, achieved complete response (CR), and subsequently developed progressive peripheral calcification with sustained remission over 6 years.

CASE PRESENTATION

Chief complaints

Case 1: A 74-year-old male presented with a liver mass evident on abdominal computed tomography (CT).

Case 2: A 71-year-old male patient presented with a liver mass evident on abdominal magnetic resonance imaging (MRI).

History of present illness

Case 1 and Case 2 were asymptomatic and both underwent imaging as screening of high risk of HCC in patient liver cirrhosis.

History of past illness

Case 1: The patient had a known case of liver cirrhosis secondary to nonalcoholic steatohepatitis.

Case 2: The patient had a known case of liver cirrhosis secondary to hepatitis C virus.

Personal and family history

Case 1 and Case 2 were unremarkable.

Physical examination

General and abdominal examinations were unremarkable for both cases.

Laboratory examinations

Case 1: Liver function test results, complete blood count, and coagulation profile were all within normal limits apart from a low count of platelets (70/µL). Seum alpha fetoprotein was within normal limits.

Case 2: Complete blood count, coagulation profile, and liver function test results were all within normal limits. Seum alpha fetoprotein was elevated (420 ng/mL).

Imaging examinations

Case 1: The patient underwent CT with intravenous contrast. It showed a 6.5 cm segment 8 hepatic mass. The mass showed well defined delineate intense arterial phase enhancement with subsequent washout in the portal venous and delayed phases within the peripheral capsule. Findings revealed a liver imaging and report and data system (LI-RADS) category 5 lesion (Figure 1).

Figure 1 Baseline computed tomography of the abdomen. A: Arterial phase computed tomography (CT) showed a large, well-defined hypervascular hepatic mass; B: Delayed phase CT demonstrated washout of the mass with an enhancing peripheral rim (tumor capsule).

Case 2: The patient underwent abdominal MRI. It showed a 6 cm segment 7 hepatic mass. It showed intense arterial phase enhancement with subsequent washout in the portal venous and delayed phases. Findings revealed an LI-RADS category 5 lesion (Figure 2).

Figure 2 Baseline magnetic resonance imaging of the abdomen. A: Arterial phase T1-weighted magnetic resonance imaging showed a large, well-defined, arterially enhancing hepatic mass; B: Delayed phase T1-weighted magnetic resonance imaging demonstrated washout of the lesion.

FINAL DIAGNOSIS

Case 1

A case of large solitary HCC with preserved liver function and no vascular invasion or extrahepatic metastasis (early stage).

Case 2

A case of large solitary HCC with preserved liver function and no vascular invasion or extrahepatic metastasis (early stage).

TREATMENT

Case 1

TACE, as a bridging and downstaging therapy prior to liver transplantation, was recommended after discussion with the HCC tumor board. The first session of DEB-TACE was performed using 150 mg doxorubicin loaded into two vials of 100-300 µm drug-eluting microspheres (DC Bead). Due to a partial response (PR), a second DEB-TACE session was performed using 75 mg doxorubicin loaded into one vial of 100-300 µm drug-eluting microspheres (Figure 3).

Figure 3 Digital subtraction angiography images during the first drug-eluting bead transarterial chemoembolization session in Case 1. A: Right hepatic artery non-selective angiogram; B: Selective hepatic angiogram showed a hypervascular mass; C: Superselective angiogram demonstrated complete stasis of the vascular supply of the tumor after embolization.

Case 2

After discussion with the HCC tumor board, TACE was recommended as a bridging and downstaging therapy prior to liver transplantation. The first session of DEB-TACE was performed using 150 mg doxorubicin loaded into two vials of 100-300 µm drug-eluting microspheres (DC Bead). Due to a PR, a second DEB-TACE session was performed using 75 mg doxorubicin loaded into one vial of 100-300 µm drug-eluting microspheres (Figure 4).

Figure 4 Digital subtraction angiography images during the first drug-eluting bead transarterial chemoembolization session in Case 2. A: Celiac angiogram showed a large hypervascular hepatic mass; B: Right hepatic lobar angiogram showed tumor supply by multiple right hepatic artery branches; C: Post-embolization angiogram demonstrated complete stasis of tumor supply.

OUTCOME AND FOLLOW-UP

Case 1

The first follow-up CT after 6 weeks of TACE revealed PR (Figure 5). The second follow-up CT after the second session revealed CR (Figure 6). The 1-year follow-up CT demonstrated CR with peripheral faint hyperdensities, suggesting early calcification (Figure 7). The patient was deemed ineligible for liver transplantation due to advanced age. He was actively monitored with clinical, laboratory, and imaging examinations. The 6-year follow-up CT demonstrated sustained CR with progressive peripheral hyperdensities encircling the tumor, consistent with concentric calcifications (Figure 8).

Figure 5 Six-week follow-up computed tomography of the abdomen after the first drug-eluting bead transarterial chemoembolization in Case 1. A: Arterial phase computed tomography (CT) showed a residual hypervascular nodule at the periphery of the non-enhancing treated mass, indicating partial response; B: Delayed phase CT confirmed washout of the residual soft tissue nodule.

Figure 6 Four-week follow-up computed tomography of the abdomen after the second drug-eluting bead transarterial chemoembolization in Case 1. A: Arterial phase computed tomography (CT) showed a non-enhancing mass, consistent with complete response; B: Portal venous phase CT demonstrated normal hepatic parenchymal enhancement with a necrotic treated mass.

Figure 7 One-year follow-up computed tomography of the abdomen after the second drug-eluting bead transarterial chemoembolization in Case 1. A: Pre-contrast computed tomography (CT) demonstrated faint linear peripheral calcification of the treated hepatic mass; B: Arterial phase CT showed a non-enhancing mass, consistent with complete response.

Figure 8 Six-year follow-up computed tomography of the abdomen after the second drug-eluting bead transarterial chemoembolization in Case 1. A: Pre-contrast computed tomography (CT) demonstrated progressive peripheral concentric calcification encircling the treated hepatic mass; B: Arterial phase CT showed a non-enhancing mass, consistent with sustained complete response.

Case 2

The first follow-up MRI, performed 8 weeks after TACE, demonstrated PR (Figure 9). The subsequent CT after the second TACE session revealed CR (Figure 10). The 1-year follow-up CT demonstrated CR with peripheral faint hyperdensities, consistent with early calcification (Figure 11). The patient declined liver transplantation as the tumor had achieved CR. He was enrolled in routine clinical, laboratory, and imaging follow-up. The 6-year follow-up CT demonstrated sustained CR with progressive peripheral concentric calcifications (Figure 12). Serum alpha-fetoprotein normalized after the second TACE session and remained within normal limits.

Figure 9 Eight-week follow-up magnetic resonance imaging of the abdomen after the first drug-eluting bead transarterial chemoembolization in Case 2. A: Arterial phase magnetic resonance imaging showed a residual hypervascular nodule at the periphery of the treated mass, indicating partial response; B: Delayed phase magnetic resonance imaging demonstrated washout of the residual soft tissue nodule.

Figure 10  Six-week follow-up computed tomography of the abdomen after the second drug-eluting bead transarterial chemoembolization in Case 2. A: Arterial phase computed tomography (CT) showed a non-enhancing treated mass, consistent with complete response; B: Portal venous phase CT demonstrated normal hepatic parenchymal enhancement with a necrotic treated mass.

Figure 11  One-year follow-up computed tomography of the abdomen after the second drug-eluting bead transarterial chemoembolization in Case 2. A: Pre-contrast computed tomography (CT) demonstrated faint linear peripheral calcification of the treated hepatic mass; B: Arterial phase CT showed a non-enhancing mass, consistent with complete response.

Figure 12  Six-year follow-up computed tomography of the abdomen after the second drug-eluting bead transarterial chemoembolization in Case 2. A: Pre-contrast computed tomography (CT) demonstrated dense, progressive peripheral concentric calcification surrounding the treated hepatic mass; B: Arterial phase CT showed a non-enhancing mass, consistent with sustained complete response.

DISCUSSION

Although traditionally considered a palliative option, TACE can achieve curative intent in carefully selected patients. A prospective cohort demonstrated durable management of early-stage HCC using super-selective TACE[28], and several retrospective series have reported overall survival comparable with radiofrequency ablation in patients within the Milan criteria when ablation or surgery is contraindicated[29,30].

The optimal therapeutic objective of TACE is complete tumor necrosis[31,32]. Radiological CR, which is the strongest predictor of long-term survival[33,34], can even predict outcomes following subsequent curative treatments, such as transplantation when TACE is used as a bridge therapy[35]. Imaging characteristics of HCC can predict the likelihood of response: Well-circumscribed capsulated hypervascular HCCs ≤ 5 cm supplied by a dominant arterial feeder respond best, whereas ill-defined, infiltrative, hypovascular tumors > 5 cm seldom demonstrate CR[36,37].

Assessment of HCC treatment response using response evaluation criteria in solid tumor (RECIST) based on tumor shrinkage often underestimate response in HCC as they disregard tumor necrosis[31,32]. The modified RECIST (mRECIST) criteria based on contrast-enhanced CT or MRI to measure viable, enhancing tumor tissue are now the most widely accepted method and are endorsed by international guidelines[18,31]. The response is categorized as CR defined by the disappearance of all enhancing lesions or PR defined as at least a 30% reduction in enhancing tumor diameter[38]. Multiple studies show that objective response by mRECIST, particularly CR, is strongly associated with improved overall survival, making it a reliable prognostic factor and validated endpoint in HCC trials[34,35].

The prognosis, however, depends not only on controlling the tumor burden but also on preserving underlying liver function. Achieving high objective response rates and minimizing collateral hepatic injury are equally important for improving survival and maintaining quality of life[39-42]. Super-selective DEB-TACE fulfils both aims by delivering higher intratumoral drug concentration, enhancing better local control, and reducing systemic toxicity and non-target embolization of the healthy liver[43,44].

Post-treatment tumor calcification has been described in several malignancies, including colorectal liver metastases and ovarian cancers in which it often reflects dystrophic calcification of necrotic tissue and has been associated with favorable prognosis[45].

In HCC calcification following locoregional therapy is exceedingly rare. Calcification after transarterial radioembolization has been reported and was associated with better prognosis, suggesting its potential role as an early surrogate marker of CR[26]. Conversely, only a single case report has described dystrophic calcification after DEB-TACE, likely related to treatment-induced tissue injury[25]. In my cases DEB-TACE likely induced extensive coagulative necrosis leading to peripheral calcification that was unmasked by the absence of lipiodol.

Although the exact pathogenesis remains uncertain, tumoral calcification after TACE is generally considered a manifestation of dystrophic calcification within necrotic tissue rather than a process specific to DEB-TACE. Necrotic cells release phosphate ions that combine with calcium salts in an alkaline environment, and in the absence of normal blood supply and cellular inhibitory mechanisms, these salts precipitate and deposit. This mechanism explains the peripheral sickle-like or ring-like calcification pattern observed that may serve as a surrogate marker of effective therapy as demonstrated in my cases[25,46,47].

The association between calcification and long-term remission in my cases suggests that calcification may represent a late imaging marker of effective tumor necrosis. However, both patients had already achieved CR based on mRECIST prior to the appearance of calcification, and CR remains the most reliable predictor of outcome[33,34]. Thus, calcification should be considered a hypothesis-generating observation rather than a validated biomarker, underscoring the need for prospective studies to clarify whether it has independent prognostic significance.

This report has some limitations. It describes only 2 highly selected patients with favorable prognostic features, limiting its generalizability. As a case report it cannot establish causality between calcification and outcome. Nevertheless, the rarity of calcification after DEB-TACE and the unusually long survival observed in my patients make these cases valuable for raising awareness of this potential imaging marker.

CONCLUSION

While TACE is generally regarded as a palliative option, my cases demonstrated that with appropriate patient selection and technique CR and durable remission are achievable even in large HCCs. The appearance of peripheral tumoral calcification following DEB-TACE may represent a late imaging marker of effective tumor necrosis and durable disease control although this observation remains hypothesis-generating and requires validation in larger cohorts. These findings suggest that calcification after DEB-TACE could serve as a potential imaging biomarker of treatment success. Further prospective studies are warranted to clarify its prognostic value and validate its clinical significance.

ACKNOWLEDGEMENTS

The author thanks the interventional radiology nursing and technologist team at King Saud University Medical City for their assistance during patient procedures and follow-up care.